All ETDs from UAB

Advisory Committee Chair

Laura Volpicelli-Daley

Advisory Committee Members

Shaida Andrabi

Rita Cowell

Gwendalyn King

Rosalinda Roberts

Document Type

Dissertation

Date of Award

2022

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Mitochondrial dysfunction, transcriptional dysregulation, and protein aggregation are all unifying features of neurodegenerative disorders, including Parkinson’s Disease. Parkinson’s Disease is a debilitating movement disorder with no known cure, leading sci-entists to explore the underlying etiological contributors to neuronal dysfunction and loss to devise strategies for neuroprotection. Estrogen-related receptor gamma (ERRγ) is a member of a family of transcription factors which regulate the expression of mitochondrial genes. To determine whether ERRγ modulation can provide insight into transcriptional and mitochondrial dysfunction with neurodegeneration, the experiments in this thesis project determined 1) the importance of transcription of mitochondrial genes in disease as regu-lated by ERRγ in neurons, 2) the role of ERRγ in adult dopaminergic neurons, 3) ERRγ’s importance in maturation of dopaminergic neurons, and 4) ERRγ’s function in spiny pro-jection neurons in the striatum. ERRγ is expressed throughout the brain in all neuron types including the dopaminergic midbrain population that is lost in Parkinson’s Disease and the GABAergic spiny projection population where dopaminergic neurons project. To be able to determine the role of ERRγ in specific neuronal populations, since ERRγ null mice die perinatally, the use of Cre-lox technology was essential to test these hypotheses. To under-stand the functional consequence of the deletion of ERRγ in these neuron types we used behavioral assays, quantitative real-time PCR, immunofluorescence, fluorescent in situ hy-bridization, high performance liquid chromatography, and RNA sequencing. Using these iv techniques, we demonstrate an important role of ERRγ in a model of Parkinson’s Disease with overexpression providing protection in striatum dopaminergic projections, and knock-out exacerbating cell loss. We also determine a novel role of ERRγ in spiny projection neurons to regulate the expression of immediate early genes that are important for neurons in their response to stimulus. The data in the following chapters demonstrate ERRγ’s important role in dopaminergic neurons that differ from GABAergic spiny projection neurons, both of which are effected by ERRγ ablation or overexpression and show importance for disease progression, neuronal specification, and activity-dependent responses. Together, these data indicate the importance of ERRγ in the regulation of transcription in neurons and its potential as a therapeutic target for neurodegeneration.

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